1. Department of neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
2. Department of neurology, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, China
3. Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, 58105, USA
4. Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University, Shanghai 200025, China
Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease. To date, there is no any effective pharmacological treatment for improving patients' symptoms and quality of life. Rapidly emerging evidence suggests that C-terminal fragments (CTFs) of TAR DNA-binding protein of 43 kDa (TDP-43), including TDP-35 and TDP-25, may play an important role in ALS pathogenesis. Valproate (VPA), a widely used antiepileptic drug, has neuroprotective effects on neurodegenerative disorders. As for ALS, preclinical studies also provide encouraging evidence for multiple beneficial effects in ALS mouse models. However, the potential molecular mechanisms have not been explored. Here, we show protective effects of VPA against TDP-43 CTFs-mediated neuronal toxicity and its underlying mechanisms in vitro. Remarkably, TDP-43 CTFs induced neuronal damage via endoplastic reticulum (ER) stress-mediated apoptosis. Furthermore, autophagic self-defense system was activated to reduce TDP-43 CTFs-induced neuronal death. Finally, VPA attenuated TDP-25-induced neuronal toxicity via suppressing ER stress-mediated apoptosis and enhancing autophagy. Taken together, these results demonstrate that VPA exerts neuroprotective effects against TDP-43 CTFs-induced neuronal damage. Thus, we provide new molecular evidence for VPA treatment in patients with ALS and other TDP-43 proteinopathies.
Keywords: Amyotrophic lateral sclerosis, Valproate, 25 kDa C-terminal fragment of TDP-43, Endoplasmic reticulum stress, Autophagy